The present invention relates to the field of L-nucleosides.
The last few decades have seen significant efforts expended in exploring possible uses of D-nucleoside analogs as antiviral agents. Some of this work has borne fruit, and a number of nucleoside analogs are currently being marketed as antiviral drugs, including the HIV reverse transcriptase inhibitors (AZT, ddI, ddC, d4T, and 3TC).
Nucleoside analogs have also been investigated for use as immune system modulators, (Bennet, P. A. et al., J. Med. Chem., 36, 635, 1993), but again with less than completely satisfactory results. For example, guanosine analogs such as 8-bromo-, 8-mercapto-, 7-methyl-8-oxoguanosine (Goodman, M. G. Immunopharmacology, 21, 51-68, 1991) and 7-thia-8-oxoguanosine (Nagahara, K. J. Med. Chem., 33, 407-415, 1990; U.S. Pat. No. 5,041,426) have been studied over the years for their ability to activate the immune system. These guanosine derivatives show excellent antiviral and/or antitumor activity in vivo. But, these C8-substituted guanosines were unable to activate T-cells (Sharma, B. S. et al., Clin. Exp. Metastasis, 9, 429-439, 1991). The same was found to be true with 6-arylpyrimidinones (Wierenga, W. Ann. N. Y. Acad. Sci., 685, 296-300, 1993). In other research, a series of 3-deazapurine nucleosides were synthesized and evaluated as immuno-modulating agents. U.S. Pat. No. 4,309,419 describes the use of 3-deazaadenosine as being an inhibitor of the immune system. The xcex2-D-nucleoside, xcex2-2xe2x80x2-deoxy-3-deazaguanosine (U.S. Pat. No. 4,950,647) displayed the most potent immunoenhancing potency on activated T-cell response. Antiinflamatory and immunosuppressant activity has also been disclosed for certain 2xe2x80x2-deoxynucleosides (EPO Application 0 038 569). However, these compounds undergo facile in vivo metabolic cleavage of their glycosyl bond, which effectively inactivates their biological potency. Adenosine derivatives disclosed in U.S. Pat. No. 4,148,888 are also catabolized in vivo by deaminase enzymes. In still other research, Levamisole, a thymomimetic immunostimulant (Hadden et al, Immunol. Today, 14, 275-280, 1993), appears to act on the T-cell lineage in a manner similar to thymic hormones. Tucaresol (Reitz et al, Nature, 377, 71-75,1995), another T-cell stimulant, is now undergoing clinical trials. More recently, 6-substituted purine linker amino acid (Zacharie et al, J. Med. Che., 40, 2883-2894, 1997) has been described as a promising immunostimulant which may be targeted for those disease states which require an increased CTL or Th1 type response.
One possible target of immunomodulation involves stimulation or suppression of Th1 and Th2 lymphokines. Type I (Th1) cells produce interleukin 2 (IL-2), tumor necrosis factor (TNFxcex1) and interferon gamma (IFNxcex3) and they are responsible primarily for cell-mediated immunity such as delayed type hypersensitivity and antiviral immunity. Type 2 (Th2) cells produce interleukins, IL4, IL-5, IL-6, IL-9, IL-10 and IL-13 and are primarily involved in assisting humoral immune responses such as those seen in response to allergens, e.g. IgE and IgG4 antibody isotype switching (Mosmann, 1989, Annu Rev Immunol, 7:145-173). D-guanosine analogs have been shown to elicit various effects on lymphokines IL-1, IL-6, IFNxcex1 and TNFxcex1 (indirectly) in vitro (Goodman, 1988, Int J Immunopharmacol, 10, 579-88) and in vivo (Smee et al., 1991, Antiviral Res 15: 229). However, the ability of the D-guanosine analogs such as 7-thio-8-oxoguanosine to modulate Type I or Type 2 cytokines directly in T cells was ineffective or has not been described.
Significantly, most of the small molecule research has focused on the synthesis and evaluation of D-nucleosides. This includes Ribavirin (Witkowski, J. T. et al., J. Med. Chem., 15, 1150, 1972), AZT (De Clercq, E. Adv. Drug Res., 17, 1, 1988), DDI (Yarchoan, R. et al., Science (Washington, D.C.), 245, 412, 1989), DDC (Mitsuya, H. et al., Proc. Natl. Acad. Sci. U.S.A., 83, 1911, 1986), d4T (Mansuri, M. M. et al., J. Med. Chem., 32, 461, 1989) and 3TC (Doong, S. L. et al., Proc. Natl. Acad. Sci. U.S.A., 88, 8495-8599, 1991). In this handful of therapeutic agents, only 3TC which contains an unnatural modified L-ribose moiety, the enantiomer of natural D-ribose.
After the approval of 3TC by the FDA, a number of nucleosides with the unnatural L-configuration were reported as having potent chemotherapeutic agents against immunodeficiency virus (HIV), hepatitis B virus (HBV), and certain forms of cancer. These include (xe2x88x92)-xcex2-L-1-[2-(hydroxymethyl)-1,3-oxathiolan-4-yl]-5-fluorocytosine (FTC; Furman, P. A., et al, Antimicrob. Agents Chemother., 36, 2686-2692, 1992), (xe2x88x92)-xcex2-L-2xe2x80x2,3xe2x80x2-dideoxypentofuranosyl-5-flurocytosine (L-FddC; Gosselin, G., et al, Antimicrob. Agents Chemother., 3-8, 1292-1297, 1994), (xe2x88x92)-xcex2-L-1-[2-(hydroxymethyl)-1,3-oxathiolan-4-yl]cytosine [(xe2x88x92)-OddC; Grove, K. L., et at, Cancer Res., 55, 3008-3011, 1995], 2xe2x80x2,3xe2x80x2-dideoxy-xcex2-L-cystidine (xcex2-L-ddC; Lin, T. S., et at, J. Med. Chem., 37, 798-803, 1994), 2xe2x80x2fluoro-5-methyl-xcex2-L-arabinofuiranosyluracil (L-FMAU; U.S. Pat. No. 5,567,688), 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydro-xcex2-L-cystidine (xcex2-L-d4C; Lin, T. S., et al, J. Med. Chem., 39, 1757-1759, 1996), 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydro-xcex2-L-5-fluorocystidine (xcex2-L-Fd4C; Lin, T. S., et al, J. Med. Chem., 39, 1757-1759, 1996), L-cyclopentyl carbocyclic nucleosides (Wang, P., et al, Tetrahedron Letts., 38, 4207-4210, 1997) and variety of 9-(2xe2x80x2-deoxy-2xe2x80x2-fluoro-(xcex2-L-arabinofiaranosyl)purine nucleosides (Ma, T."" et al, J. Med. Chem., 40 2750-2754, 1997).
Other research on L-nucleosides has also been reported. U.S. Pat. No. 5,009,698, for example, describes the synthesis and use of L-adenosine to stimulate the growth of a plant. WO 92/08727 describes certain L-2xe2x80x2-deoxyuridines and their use for treating viruses. Spadari, S. et at, J. Med. Chem., 35, 4214-4220, 1992, describes the synthesis of certain L-xcex2-nucleosides useful for treating viral infections including Herpes Simplex Virus Type I. U.S. Pat. No. 5,559,101 describes the synthesis of xcex1- and xcex2-L-ribofuranosyl nucleosides, processes for their preparation, pharmaceutical composition containing them, and method of using them to treat various diseases in mammals. A German patent (De 195 18 216) describes the synthesis of 2xe2x80x2-fluoro-2xe2x80x2-deoxy-L-xcex2-arabinofuiranosyl pyrimidine nucleosides. U.S. Pat. Nos. 5,565,438 and 5,567,688 describe the synthesis and utility of L-FMAU. WO Patent 95/20595 describes the synthesis of 2xe2x80x2-deoxy-2xe2x80x2-fluoro-L-xcex2-arbinofuranosyl purine and pyrimidine nucleosides and method of treating HBV or EBV. U.S. Pat. No. 5,567,689 describes methods for increasing uridine levels with L-nucleosides. WO patent 96/28170 describes a method of reducing the toxicity of D-nucteosides by co-administering an effective amount of L-nucleoside compounds.
Significantly, while some of the known L-nucleosides have shown potent antiviral activity with lower toxicity profiles than their D-counterparts, none of these L-nucleoside compounds have been shown to posses immunomodulatory properties. Moreover, at present there is no effective treatment for the modulation of the immune system where lymphokine profiles (Th1 and Th2 subsets) have been implicated. Thus, there remains a need for novel L-nucleoside analogs, especially a need for L-nucleoside analogs which modulate the immune system, and most especially L-nucleoside analogs which specifically modulate Th1 and Th2.
The present invention is directed to novel L-nucleoside compounds, their therapeutic uses and synthesis.
In one aspect of the invention, novel L-nucleoside compounds are provided according to the following formula: 
wherein:
A is independently selected from N or C;
B, C, E, F are independently selected from CH, CO, N, S, Se, O, NR1, CCONH2, CCH3, Cxe2x80x94R2 or P; R1 is independently H, lower alkyl, lower alkylamines, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls. R2 is independently H, OH, halogens, CN, N3, NH2, C(xe2x95x90O)NH2, C(xe2x95x90S)NH2, C(xe2x95x90NH)NH2.HCl, C(xe2x95x90NOH)NH2, C(xe2x95x90NH)OMe, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles;
D is independently selected from CH, CO, N, S, Se, O, NR1, CCONH2, CCH3, Cxe2x80x94R2, P or nothing, where R1 is independently H, O, lower alkyl, lower alkylamines, COCH3, lower alkyl alkenyl, lower alkyl vinyl or lower alkyl aryls, and R2 is independently H, OH, halogens, CN, N3, NH2, lower alkyl, lower alkylamines, lower alkyl alkenyl, lower alkyl vinyl, lower alkyl aryls or substituted heterocycles;
X is independently O, S, CH2 or NR; where R is COCH3;
R1 and R4 are independently selected from H, CN, N3, CH2OH, lower alkyl and lower alkyl amines;
R2, R3, R5, R6, R7 and R8 are independently selected from H, OH, CN, N3, halogens, CH2OH, NH2, OCH3, NHCH3, ONHCH3, SCH3, SPh, alkenyl, lower alkyl, lower alkyl amines and substituted heterocycles; and
R1, R2, R3, R4, R5, R6, R7 and R8 are not all substituted at the same time; such that
when R2=R3=H, then R7 and R8 are hydrogens or nothing;
when R1, R4 or R5 are substituted, then R7=R8=H and R2=R3=OH;
when R2 or R3 are substituted, then R7 and R8 are H or OH;
when R7 or R8 are substituted, then R2 and R3 are H or OH;
when R7 and R8 are hydroxyl, then R2 and R3 are not OH;
when Axe2x95x90N; Bxe2x95x90CO; Cxe2x95x90N or NH; Dxe2x95x90CO or Cxe2x80x94NH2; E is CH or C-substituted; Fxe2x95x90CH; Xxe2x95x90O, S or CH2, then R2 will not be H, OH, CH3, halogens, N3, CN, SH, SPh, CH2OH, CH2OCH3, CH2SH, CH2F, CH2N3, aryl, aryloxy or heterocycles;
when Axe2x95x90N; Bxe2x95x90CO; Cxe2x95x90N or NH; Dxe2x95x90CO or Cxe2x80x94NH2; E is CH, Cxe2x80x94CH3 or halogen; Fxe2x95x90CH; Xxe2x95x90Nxe2x80x94COCH3, then R2 will not be H or OH;
when Axe2x95x90N; Bxe2x95x90CH; Cxe2x95x90CH or CH3; Dxe2x95x90CH or Cxe2x80x94CH3; E is CH, Cxe2x80x94CH3 or Cxe2x80x94CONH2; Fxe2x95x90CH; Xxe2x95x90O, or CH2, then R2 will not be H or OH;
when Axe2x95x90N; Bxe2x95x90N, CO or CH; Cxe2x95x90CH, Cxe2x80x94Cl or Cxe2x80x94OCH3; Dxe2x95x90CH or Cxe2x80x94Ph; E is CH, Cxe2x80x94Cl or Cxe2x80x94Ph; Fxe2x95x90N or CO; Xxe2x95x90O, then R2 will not be H or OH;
when Axe2x95x90N; Bxe2x95x90CO or CS; Cxe2x95x90N or NH; Dxe2x95x90CO or Cxe2x80x94NH2; E is CH or N; Fxe2x95x90N or CH; Xxe2x95x90O, then R2 will not be H or OH; and
when Axe2x95x90C; Bxe2x95x90CH; Cxe2x95x90NH; Dxe2x95x90CO, CS or Cxe2x80x94NH2; E is N or NH; Fxe2x95x90CO or CH; Xxe2x95x90O, then R2 will not be H or OH.
In one class of preferred embodiments of the invention, the compound comprises a ribofuiranosyl moiety, and in a particularly preferred embodiment the compound comprises L-Ribavirin.
In another aspect of the invention, a pharmaceutical composition comprises a therapeutically effective amount of a compound of Formulas 1 and 3-5, or a pharmaceutically acceptable ester or salt thereof admixed with at least one pharmaceutically acceptable carrier.
In yet another aspect of the invention, a compound according to Formulas 1 and 3-5 is used in the treatment of any condition which responds positively to administration of the compound, and according to any formulation and protocol which achieves the positive response. Among other things it is contemplated that compounds of Formula I may be used to treat an infection, an infestation, a cancer or tumor or an autoimmune disease.